Various compounds have been described as inhibitors of human immunodeficiency virus type 1 (HIV-1) in vitro and are targeted at the virus-encoded reverse transcriptase (RT), e.g., nevirapine, pyridinone, TIBO, BHAP, TSAO, and quinoxaline. The selectivity of these compounds for HIV-1 is due to a highly specific interaction with HIV-1 RT.
The rapid emergence of HIV-1 strains resistant to several HIV-1-specific RT inhibitors in cell culture and in AIDS patients has caused concern for further development of these inhibitors in the clinic. However, HIV-1 resistance to one HIV-1-specific RT inhibitor does not necessarily imply cross-resistance to other HIV-1-specific RT inhibitors. Indeed, it has been proven that HIV-1-specific RT inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in their RT. For example, HIV-1 strains containing the 100 Leu.fwdarw.Ile mutation in their RT are resistant to TIBO R82913 and R82150 but not to nevirapine and the TSAO derivatives TSAO-T and TSAO-m.sup.3 T. Also, HIV-1 strains containing the 138 Glu.fwdarw.Lys mutation in their RT are resistant to TSAO derivatives but not to the other HIV-1-specific RT inhibitors, such as BHAP and nevirapine. In contrast, the 181 Tyr.fwdarw.Cys mutation in the RT of HIV-1 strains renders the mutant viruses resistant to virtually all HIV-1 specific RT inhibitors described to date except certain oxathiin carboxanilide derivatives described in U.S. Pat. No. 5,268,239. See, e.g., Balzarini et al, J. Virology 67(9): 5353-5359 (1993) ("Balzarini I") and Balzarini et al, Virology 192: 246-253 (1993) ("Balzarini II").
Unsuccessful attempts have been made to combine various HIV-1 RT inhibitors to eliminate virus resistance. See, e.g., Balzarini I.
Accordingly, it is the purpose of this invention to provide a composition comprising a combination of certain HIV RT inhibitor compounds which can inhibit or suppress the emergence of drug-resistant HIV-1 strains.
It is also the purpose of this invention to provide a method of preventing or treating HIV-1 infections by administration of this combination of certain HIV RT inhibitor compounds.